Aziridines are basic, three-membered nitrogen containing heterocycles that resemble their oxygen counterpart epoxides in terms of chemical reactivity and structure. Aziridines like other three membered ring-systems are highly strained with ˜60° bond angles. As a consequence, aziridines undergo highly regio- and stereoselective transformations. Due to their utility aziridines are highly sought after useful entities that are frequently employed by synthetic chemists in agrochemical, pharmaceutical, medicinal, materials and academic laboratories alike. Further substantiating their pre-eminence, aziridines are often employed as key intermediates in the synthesis of unnatural α- and β-amino acids, chiral auxiliaries, polymers, azasugars and heterocyclic entities such as oxazolidinones, imidazolidines, β-lactams, thioxazolidinethiones and pyrrolidines. Furthermore, aziridines are powerful alkylating agents. Many synthetic and natural product derived aziridines have potent anti-tumour, anti-viral and/or anti-bacterial properties, examples being the Azinomycins, Ficellomycin, Miraziridine, Maduropeptin, PBI-A, Mitomycin A, FR66979 and NSC 639823. Therefore the development of aziridine syntheses that are efficient, high yielding, mild, environmentally friendly and amenable to the formation of structurally diverse entities is extremely important.
Accordingly, a plethora of racemic and optically active synthetic protocols have been developed for the generation of aziridines. In the main the synthetic approaches can be categorised as: cyclisation reactions, transfers of nitrogen to olefins, transfers of carbon to imines, additions across the carbon-nitrogen double bond of azirines, reactions of ylids, aza-Darzen approaches, ring contraction and functional group transformations. Of these, aziridination via carbene transfer to N-substituted imines has proven particularly popular.
The reaction of a carbene with a Schiff base to afford an aziridine has been known since the 1970s. Baret et al. (Bull. Soc. Chem. Fr., 1972, p. 2493) reported aziridine formation when an imine was allowed to react with ethyl diazoacetate in the presence of copper powder. Similarly, performing a Simmons-Smith reaction incorporating an imino ester also afforded aziridines (Baret et al., Bull. Soc. Chem. Fr., 1972, p. 825).
The methodology has since been extended to chiral synthesis. For example, in 1995 Hansen et al. (Angew. Chem. Int. Ed. Engl., 1995, vol. 34, p. 676) reported that ethyl diazoacetate reacted with diphenylimine in the presence of a catalytic quantity of a chiral non-racemic copper(I) bis(oxazoline) complex 1 [derived from (S)-phenylglycine].

The reaction afforded the desired chiral non-racemic N-phenylaziridines as their cis-/trans-diastereoisomers (2 and 3 respectively, Scheme 1) with modest stereoinduction (22-67% e.e.). In addition to the desired aziridines, varying amounts (i.e. ˜10%) of a racemic pyrrolidine 4 was generated as an unwanted by-product (Scheme 1). Further draw-backs to this procedure are the incorporation of the toxic and hence environmentally unfriendly copper salt and the fact that cleavage of the N-phenyl substituent, affording the corresponding NH-aziridine, without recourse to ring-opening the aziridine ring is extremely challenging.
Stemming from the above, a wide range of metal based Lewis acids have been employed for the activation and subsequent reaction of N-substituted imines with alkyl diazoacetates to afford the corresponding aziridines in 42-93% yields. Examples of the Lewis acids that have been investigated include aluminium chloride, titanium(IV) chloride, tin(IV) chloride, methylrhenium trioxide, lanthanide triflates, indium trichloride, [(η2-C5H5)Fe(CO)2(THF)]+BF4− and [Mo(OTf)(η3-C3H5)(CO)2(phen)].
The use of such catalysts however incurs a number of serious draw-backs such as the generation of metal-contaminated waste which may well present potential disposal issues and increase the environmental impact of the chemistry. In general many of the metal-mediated processes have limited substrate scope potential, and many require relatively high loadings of the metal salt and/or the ligand, a fact that further exacerbates disposal and environmental problems, and increases the overall costs of the chemistry undertaken. Additionally many of the metals employed are toxic, difficult to handle and store and would, if an accident were to occur, present significant health and disposal problems. Due to their often highly reactive nature towards water or damp air, the reaction conditions for their use require absolutely anhydrous reaction conditions to be maintained at all times, otherwise significantly reduced yields result. Furthermore, the reactive nature of these Lewis acids often results in significant degradation of the aziridines giving lower yields. The knock on effect of this is that subsequent purification of the desired products can be complicated, a fact that again increases the environmental impact of aziridine synthesis.
In view of the above, a few researchers have sought to avoid the difficulties associated with the use of metal based Lewis acid catalysts by employing organic molecules as ‘organocatalysts’, albeit with varying success. Many of these ‘organic mediated’ procedures are also not ideal and the majority have severe experimental and/or substrate limitations.
Taking the lead in this field, Antilla et al. (Angew. Chem. Int. Ed., 2000, vol. 39(24), pp. 4518-4520) have reported a procedure (Scheme 2) that requires the synthesis of an expensive precatalyst 5 (˜£450 per mmol) that is only usable when transformed into its active form 6. From a practical point of view it would be preferable that the catalyst 6 be stable and storable in a bottle, on a shelf ready to be used as and when required; unfortunately this is not the case. The procedure further requires the use of relatively high (˜10 mol %) amounts of catalyst and the transformation of 5 into 6 is also demanding requiring 3-4 equivalents of the triphenylborate.

Others, such as Akiyama et al. (Organic Letters, 2009, vol. 11(11), pp. 2445-2447) and Zeng et al. (Organic Letters, 2009, vol. 11(14), pp. 3036-3039) have employed chiral phosphoric acids as catalysts, as illustrated below (Schemes 3 and 4).

Whilst the use of chiral phosphoric acids overcomes some of the storage problems associated with the Antilla procedure, a number of other difficulties still remain. In particular, the efficacy of the chiral phosphoric acids is highly dependent upon the nature of the starting material substrates. For instance the reaction will not proceed where a group such as a benzyl group is attached to the nitrogen atom of the imine. This in turn can lead to the use of N-protecting groups such as Boc groups which are difficult to remove without ring-opening the aziridine.
Furthermore, the phosphoric acid catalyst often results in significant degradation of the desired aziridines. Indeed, in the procedure set out by Zeng et al., high percentages of undesired enamine species such as 21 are generated. Thus careful purification and/or dilute reaction conditions are required, a fact that again increases the environmental impact and, inevitably, results in lower yields of the desired aziridines.
In view of the above, there is a need for further methods of synthesising aziridines to be developed, which avoid the use of metal based Lewis acid catalysts yet also overcome many of the disadvantages associated with the organocatalytic techniques discussed above.
One technique, disclosed by Hashimoto et al. (Journal of the American Chemical Society, 2011, vol. 133, pp. 9730-9733), employs the use of a chiral N-triflyl phosphoramide to catalyse the synthesis of trisubstituted aziridines from N-α-diazoacyl oxazolidinones and N-boc imines.
There is also a need for methods of synthesising isotopically labelled aziridines which allow for the regio- and stereo-specific introduction of isotopic labels into the aziridine ring, or into groups attached to the aziridine ring. Isotopically labelled compounds so-produced would find particular application in the field of nuclear medicine and/or pharmacological studies.
A particular challenge is the stereo-specific synthesis of aziridines that have pseudo-meso isotopic stereoisomers. In other words, the stereo-specific synthesis of aziridines that would be identical meso compounds were it not for their isotopic labelling. Such otherwise identical isotopic stereoisomers cannot be separated by conventional purification techniques, such as by chiral chromatography, diastereomeric crystallisation and the like, since such techniques cannot differentiate between the labelled and non-labelled atomic positions. Accordingly, stereo-specific synthesis is of vital importance if pseudo-meso isotopic stereoisomers are to be obtained in a high degree of purity.